The development of neoplasms in vertebrates is often associated with alterations in the structure or expression of cellular proto-oncogenes. We have been characterizing the cbl proto-oncogene which was first discovered in a defective retrovirus that induces pre-B lymphomas in vivo. The sequences of 3 cDNA clones (1 human and 2 mouse) show remarkable homology between the two species. One of the murine cDNAs has a 51bp internal deletion which is not due to alternative splicing. There are no nucleotide differences between v-cbl and c-cbl, rather, v-cbl is a truncated form of the gene. The sequences show c-cbl but not v-cbl to contain a leucine zipper. Sequencing of the germline locus has identified 7 exons so far, ranging in size from 120 to 201bp. A clone containing the 5' end of the gene has also been isolated and efforts to determine the regulatory sequences required for cbl expression are underway. cbl is not an immediate early gene and its expression is not regulated upon the addition of mitogens to various cell types. cbl, however, may play a role in the differention of certain cell types since terminal differentiation of erythrocytes and embryonal carcinoma stem cell shuts off cbl expression. Constructs containing either v-cbl or c-cbl have been made and will be transfected into F9 EC cells to determine the role of cbl in terminal differentiation. Both constructs have also been shown to transform NIH3T3 cells so it is not yet clear what the functional differences are between v-cbl and c-cbl. Constructs containing either v-cbl or c-cbl in conjunction with the IgH enhancer are being used to develop transgenic mice.